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There is no collection of Renaissance art on the planet that can match the Uffizi. Period. For all its crowds and other inconveniences, the Uffizi remains a must-see.

And what will you see? Some 60-plus rooms and marble corridors—built in the 16th century as the Medici’s private office complex, or uffici—all jam-packed with famous paintings, among them Giotto’s “Ognissanti Madonna,” Botticelli’s “Birth of Venus,” Leonardo da Vinci’s “Annunciation,” Michelangelo’s “Holy Family,” and many, many more.

Start with Room 2 for a look at the pre-Renaissance, Gothic style of painting. First, compare teacher and student as you examine Cimabue’s “Santa Trínita Maestà” painted around 1280, and Giotto’s “Ognissanti Madonna” ★★★ done in 1310. The similar subject and setting for both paintings allows the viewer to see how Giotto transformed Cimabue’s iconlike Byzantine style into something more real and human. Giotto’s Madonna actually looks like she’s sitting on a throne, her clothes emphasizing the curves of her body, whereas Cimabue’s Madonna and angels float in space, looking like portraits on coins, with flattened positioning and stiff angles. Also worth a look-see: Duccio’s “Rucellai Madonna” ★ (1285), one of the founding works of the ethereal Sienese School of painting.

Room 3 showcases the Sienese School at its peak, with Simone Martini’s dazzling “Annunciation” ★★ (1333) and Ambrogio Lorenzetti’s “Presentation at the Temple” (1342). The Black Death of 1348 wiped out this entire generation of Sienese painters, and most of that city’s population along with them. Room 6 shows Florentine painting at its most decorative, in the style known as “International Gothic.” The iconic work is Gentile da Fabriano’s “Procession of the Magi” ★★★ (1423). The line to see the newborn Jesus is full of decorative and comic elements, and is even longer than the one outside the Uffizi.

Room 8 contains the unflattering profiles of Duke Federico da Montefeltro of Urbino and his duchess, done by Piero della Francesca in 1472. The subjects are portrayed in an unflinchingly realistic way. The duke, in particular, exposes his warts and his crooked nose, broken in a tournament. This focus on the earthly, rather than on the Christian, elements harkens back to the teachings of classical Greek and Roman times, and is made all the more vivid by depiction (on the back) of the couple riding chariots driven by the humanistic virtues of faith, charity, hope, and modesty for her; prudence, temperance, fortitude, and justice for him.

Also here are works by Filippo Lippi from the mid–15th century. His most celebrated panel, “Madonna and Child with Two Angels” ★★, dates from around 1465. The background, with distant mountains on one side and water on the other, framing the portrait of a woman’s face, was shamelessly stolen by Leonardo da Vinci 40 years later for his “Mona Lisa.” Lippi’s work was also a celebrity scandal. The woman who modeled for Mary was said to be Filippo’s lover—a would-be nun called Lucrezia Buti whom he had spirited away from her convent before she could take vows––and the child looking toward the viewer the product of their union. That son, Filippino Lippi, became a painter in his own right, and some of his works hang in the same room. However, it was Filippo’s student (who would, in turn, become Filippino’s teacher) who would go on to become one of the most famous artists of the 15th century. His name was Botticelli.

Rooms 10 to 14—still collectively numbered as such, even though the walls were knocked down in 1978 to make one large room—are devoted to the works of Sandro Filipepi, better known by his nickname “Little Barrels,” or Botticelli. His 1485 “Birth of Venus” ★★ hangs like a highway billboard you have seen a thousand times. Venus’s pose is taken from classical statues, while the winds Zephyr and Aura blowing her to shore, and the muse welcoming her, are from Ovid’s “Metamorphosis.” Botticelli’s 1478 “Primavera” ★★★, its dark, bold colors a stark contrast to the filmy, pastel “Venus,” defies definitive interpretation (many have tried). But again it features Venus (center), alongside Mercury, with the winged boots, the Three Graces, and the goddess Flora. Next to it Botticelli’s “Adoration of the Magi” contains a self-portrait of the artist—he’s the one in yellow on the far right.

Leonardo da Vinci’s “Annunciation” ★★★ anchors Room 15. In this painting, though completed in the early 1470s while Leonardo was still a student in Verrocchio’s workshop, Da Vinci’s ability to orchestrate the viewer’s focus is masterful: The line down the middle of the brick corner of the house draws your glance to Mary’s delicate fingers, which themselves point along the top of a stone wall to the angel’s two raised fingers. Those, in turn, draw attention to the mountain in the center of the two parallel trees dividing Mary from the angel, representing the gulf between the worldly and the spiritual. Its perspective was painted to be viewed from the lower right.

Reopened after restoration in 2012, the Tribuna ★ is an octagonal room added to the Uffizi floor plan by Francesco I in the 1580s. Although visitors can no longer walk through it, you can view the mother-of-pearl ceiling and the “Medici Venus” ★, a Roman statue dating from the 1st century b.c., from outside.

As soon as you cross to the Uffizi’s west wing—past picture windows with views of the Arno River to one side and the perfect, Renaissance perspective of the Uffizi's little piazza to the other—you’re walloped with another line of masterpieces. However, it is impossible to be certain of the precise layout: The museum is undergoing a major facelift, to create the “New Uffizi.” Among the highlights of this “second half” is Michelangelo’s 1505–08 “Holy Family” ★. The twisting shapes of Mary, Joseph, and Jesus recall those in the Sistine Chapel in Rome for their sculpted nature and the bright colors. The torsion and tensions of the painting (and other Michelangelo works) inspired the next generation of Florentine painters, known as the Mannerists. Andrea Del Sarto, Rosso Fiorentino, and Pontormo are all represented in the revamped Sale Rosse (Red Rooms), opened downstairs in 2012. Here too, the Uffizi has a number of Raphaels, including his recently restored and often-copied “Madonna of the Goldfinch” ★★, with a background landscape lifted from Leonardo and Botticelli.

Titian’s reclining nude “Venus of Urbino” ★★ is another highlight of the Uffizi’s later works. It’s no coincidence that the edge of the curtain, the angle of her hand and leg, and the line splitting floor and bed all intersect in the forbidden part of her body. The Uffizi also owns a trio of paintings by Caravaggio, notably his enigmatic “Bacchus” ★, and many by the 17th- to 18th-century caravaggieschi artists who copied his chiaroscuro (bright light and dark shadows) style of painting. Greatest among them was Artemisia Gentileschi, a rare female baroque painter. Her brilliant “Judith Slaying Holofernes” ★ (ca. 1612), is one of the more brutal, bloody paintings in the gallery.

Rooms 46 to 55 also opened in 2012 to showcase the works of foreign painters in the Uffizi—the museum owns a vast and varied collection, much of which lay in storage until the opening of these new galleries. The best among these so-called Sale Blu, or “Blue Rooms,” is the Spanish gallery, with works by Goya, El Greco’s “St. John the Evangelist” (1600), and Velázquez’s “Self-Portrait” ★. Room 49 displays two of Rembrandt’s most familiar self-portraits.

If you find yourself flagging at any point (it happens to us all), there is a coffee shop at the far end of the west wing. Prices are in line with the piazza below, plus you get a great close-up of the Palazzo Vecchio’s facade from the terrace. Fully refreshed, you can return to discover works by the many great artists we didn’t have space to cover here: Cranach and Dürer; Giorgione, Bellini, and Mantegna; Uccello, Masaccio, Bronzino, and Veronese. The collection goes on and on (there are countless original Roman statues, too). There is nowhere like it in Italy, or the world.